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ABSTRACT: Bacille Calmette-Guerin (BCG) is an attenuated strain of Mycobacterium bovis that is used widely as a vaccine for tuberculosis and is used as an effective treatment for superficial bladder carcinoma. Despite being the most successful cancer biotherapy, its mechanism of action and response determinants remain obscure. Here, we establish a model system to analyze BCG interaction with bladder cancer cells, using it to show that these cells vary dramatically in their susceptibility to BCG infection. Unexpectedly, the uptake of BCG by bladder cancer cells occurs by macropinocytosis rather than phagocytosis. BCG entry into bladder cancer cells relied upon Rac1, Cdc42, and their effector kinase Pak1. The difference in susceptibility between BCG-permissive and -resistant bladder cancer cells was due to oncogenic activation of signaling pathways that activate macropinocytosis, with phosphoinositide 3-kinase inhibitor activation stimulating BCG uptake independently of Akt. Similarly, activated Ras strongly activated Pak1-dependent uptake of BCG. These results reveal that oncogenic activation of macropinocytosis determines BCG uptake by bladder cancer cells, implying that tumor responsiveness to BCG may be governed by the specific mutations present in the treated cancer cell. Cancer Res; 73(3); 1156-67. ©2013 AACR.
Cancer Research 02/2013; 73(3):1156-67. · 7.86 Impact Factor
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ABSTRACT: Immunocompromised persons with latent tuberculosis infection are at increased risk for tuberculosis reactivation compared to the general population. Tuberculin skin test, the traditional assay for diagnosing LTBI (latent tuberculosis infection), has reduced accuracy in immunocompromised patients. Interferon-gamma release assays (IGRAs) are in vitro blood tests that measure T-cell release of interferon-gamma following stimulation by antigens unique to Mycobacterium tuberculosis. Here we review the data for the use of QuantiFERON-TB Gold In-Tube (QFT-GIT) and T-SPOT.TB, the two currently available IGRAs, in immunocompromised adults, including persons infected with HIV, patients with immune-mediated inflammatory disorders, candidates for treatment with TNF (tumor necrosis factor)-α inhibitors, patients receiving hemodialysis, solid-organ transplant recipients and patients with cancer. Based on the available data IGRAs have advantages over TST in specific patient populations and in certain situations. Further studies are needed to more accurately define the utility of IGRAs in immunocompromised patients.
American Journal of Respiratory and Critical Care Medicine 12/2012; · 11.08 Impact Factor
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ABSTRACT: The tumor suppressor PTEN is a lipid phosphatase that is frequently mutated in various human cancers. PTEN suppresses tumor cell proliferation, survival, and growth mainly by inhibiting the PI3K-Akt signaling pathway through dephosphorylation of phosphatidylinositol 3,4,5-triphosphate. In addition to it role in tumor suppression, the PTEN-PI3K pathway controls many cellular functions, some of which may be important for cellular resistance to infection. Currently, the intersection between tumorigenic signaling pathways and cellular susceptibility to infection is not well defined. In this study we report that PTEN signaling regulates infection of both noncancerous and cancerous cells by multiple intracellular mycobacterial pathogens and that pharmacological modulation of PTEN signaling can affect mycobacterial infection. We found that PTEN deficiency renders multiple types of cells hyper-susceptible to infection by Mycoplasma and Mycobacterium bovis Bacillus Calmette-Guérin (BCG). The lipid phosphatase activity of PTEN is required for attenuating infection. Furthermore, we found mycobacterial infection activates host cell Akt phosphorylation, and pharmacological inhibition of Akt or PI3K activity reduced levels of intracellular infection. Intriguingly, inhibition of mTOR, one of the downstream components of the Akt signaling and a promising cancer therapeutic target, also lowered intracellular Bacillus Calmette-Guérin levels in mammary epithelial cancer MCF-7 cells. These findings demonstrate a critical role of PTEN-regulated pathways in pathogen infection. The relationship of PTEN-PI3K-Akt mTOR status and susceptibility to mycobacterial infection suggests that the interaction of mycobacterial pathogens with cancer cells may be influenced by genetic alterations in the tumor cells.
Journal of Biological Chemistry 05/2012; 287(27):23196-202. · 4.77 Impact Factor
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ABSTRACT: Bordetella bronchiseptica is a gram negative coccobacillus that can be transmitted from domestic animals and cause severe infections in immunocompromised patients. A 56-year-old man with a left parietal glioblastoma was treated with resection, radiation and concomitant and adjuvant temozolomide chemotherapy. He received bevacizumab for progression, and dose dense metronomic temozolomide was added for additional progression. He developed chronic cough and was diagnosed with B. bronchiseptica infection. This is the first reported case of B. bronchiseptica infection in a patient receiving temozolomide. The infection was likely acquired from an infected kitten. Patients receiving temozolomide should be counseled on the risks of acquiring zoonotic infections, including B. bronchiseptica, from their pets.
Journal of Neuro-Oncology 04/2011; 102(2):335-9. · 3.21 Impact Factor
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ABSTRACT: Bacterial pathogens rely on their DNA repair pathways to resist genomic damage inflicted by the host. DNA double-strand breaks (DSBs) are especially threatening to bacterial viability. DSB repair by homologous recombination (HR) requires nucleases that resect DSB ends and a strand exchange protein that facilitates homology search. RecBCD and RecA perform these functions in Escherichia coli and constitute the major pathway of error-free DSB repair. Mycobacteria, including the human pathogen M. tuberculosis, elaborate an additional error-prone pathway of DSB repair via non-homologous end-joining (NHEJ) catalysed by Ku and DNA ligase D (LigD). Little is known about the relative contributions of HR and NHEJ to mycobacterial chromosome repair, the factors that dictate pathway choice, or the existence of additional DSB repair pathways. Here we demonstrate that Mycobacterium smegmatis has three DSB repair pathway options: HR, NHEJ and a novel mechanism of single-strand annealing (SSA). Inactivation of NHEJ or SSA is compensated by elevated HR. We find that mycobacterial RecBCD does not participate in HR or confer resistance to ionizing radiation (IR), but is required for the RecA-independent SSA pathway. In contrast, the mycobacterial helicase-nuclease AdnAB participates in the RecA-dependent HR pathway, and is a major determinant of resistance to IR and oxidative DNA damage. These findings reveal distinctive features of mycobacterial DSB repair, most notably the dedication of the RecBCD and AdnAB helicase-nuclease machines to distinct repair pathways.
Molecular Microbiology 01/2011; 79(2):316-30. · 5.01 Impact Factor
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Gil Redelman-Sidi
Leukemia & lymphoma 11/2010; 51(11):1954-6. · 2.40 Impact Factor
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ABSTRACT: Rapidly growing mycobacteria (RGM) have been associated with various clinical syndromes in immunocompetent and immunocompromised hosts. The risk factors and outcomes of RGM infection in patients with cancer have not been clearly defined.
Data were derived from 2 distinct sources. Demographic and clinical data were collected for all patients with cancer at Memorial Sloan-Kettering Cancer Center with a culture positive for RGM from January 1999 through December 2008. We also reviewed the literature for studies describing RGM infection in patients with cancer.
During the 10-year period, 28 patients with cancer at Memorial Sloan-Kettering Cancer Center had cultures positive for RGM. Most cases occurred in patients with solid tumors and were confined to the lung. A review of the literature identified 313 additional patients with cancer and RGM infection. Combining our series data with cases from the literature, we defined 3 distinct syndromes: pulmonary disease, which occurred in 158 patients (47%); bloodstream infection, occurring in 151 patients (45%); and disseminated infection involving at least 1 end organ, affecting 26 persons (8%). The syndromes differed by age of onset, underlying cancer, main RGM species, and outcome. Persons with bloodstream infection typically were young and had an excellent outcome; those with disseminated infection were older, had pronounced immunosuppression, and had a very poor prognosis.
RGM infections in patients with cancer comprise 3 distinct disorders with different risk factors, predominant mycobacterial species, and prognoses. In turn, the approach to management, including number and duration of antimycobacterial drugs, may be fundamentally different for various patients with cancer who receive a diagnosis of RGM infection.
Clinical Infectious Diseases 08/2010; 51(4):422-34. · 9.15 Impact Factor
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ABSTRACT: Although usually mild, 2009 H1N1 Influenza has caused up to 6000 deaths in the US. To determine outcome in patients with cancer and/or hematopoietic stem cell transplant (HSCT), we reviewed our recent experience at Memorial Sloan-Kettering Cancer Center (MSKCC).
During the initial NYC outbreak (May 19-June 30, 2009), all respiratory samples at MSKCC were tested for 2009 H1N1 influenza by DFA, culture, and RT-PCR. Medical records were reviewed for all cases.
During the 6-week period, 45(11%) of 394 tested patients were diagnosed with 2009 H1N1 Influenza. These included 29(17%) of 167 patients with hematologic conditions compared to 16(7%) of 226 with solid tumors (P < 0.01). 21(22%) of 96 tested HSCT recipients were positive. Cough (93%) and fever (91%) were common. Of 29 patients who were radiographically assessed, 8(27%) had lower airway disease. 17(37%) were hospitalized. None required mechanical ventilation. No deaths were attributed to influenza. All treated patients tolerated antiviral medication.
2009 H1N1 Influenza caused mild symptoms in most patients with cancer and/or HSCT. None died or required mechanical ventilation. Immunosuppression from cancer or its treatment including HSCT may not be a substantial risk for poor outcome, however further studies are needed to validate our results.
The Journal of infection 02/2010; 60(4):257-63. · 4.13 Impact Factor
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ABSTRACT: Patients with advanced HIV infection commonly present with esophageal symptomatology most frequently due to Candida, cytomegalovirus, or herpes simplex virus. We present a case of a 53-year-old man with AIDS and prior esophageal candidiasis and oral aphthous ulcerations, who developed actinomycosis of the esophagus. This article aims to review clinical characteristics of this and seven previously reported cases occurring in HIV-infected patients. Esophageal actinomycosis is frequently preceded by other esophageal disease that likely results in breach of the mucosal barrier, allowing establishment of the infection. Health care providers should be aware of this rare entity, particularly in those with recurring symptoms, so that a timely diagnosis can be made.
AIDS patient care and STDs 02/2010; 24(2):73-8. · 2.68 Impact Factor
